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Elife. 2018 Apr 11;7. pii: e32893. doi: 10.7554/eLife.32893.

IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling.

Author information

1
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
2
University of Applied Sciences Upper Austria, Wels, Austria.
3
RIKEN Systems and Structural Biology Center, Yokohama, Japan.
4
RIKEN Center for Life Science Technologies, Yokohama, Japan.
5
PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan.
6
RIKEN Structural Biology Laboratory, Yokohama, Japan.
7
Austrian Competence Center for Feed and Food Quality, Safety and Innovation, Wels, Austria.

Abstract

Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS)-1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Mechanistically, IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; for this reason, IGF-IR avoids rapid endocytosis and prolongs its activity on the cell surface. Accelerating IGF-IR endocytosis via IRS-1 depletion induces the shift from sustained to transient Akt activation and augments FoxO-mediated transcription. Our study establishes a new role for IRS-1 as an endocytic regulator of IGF-IR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGF-IR signaling.

KEYWORDS:

AP2; IGF; IGF-I receptor; IRS; biochemistry; cell biology; chemical biology; clathrin; human; mouse; rat

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